Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death in the United States, is a devastating disease marked by an exceptionally high mortality rate nearly equivalent to its incidence. The median survival for a patient diagnosed with PDAC ranges from 4.5 months for the most advanced stage of the disease to 24.1 months for the earliest stage (Bilimoria et al. Cancer 2007; 110:738). Surgery is currently the treatment that provides the best chance of prolonged survival (five year survival of 20-25% vs <6% overall), however surgery is generally performed only at the earliest stages (American Cancer Society, Cancer Facts & Figures 2013). In the US, only about 15-20% of pancreatic cancer cases are diagnosed early enough to be eligible for surgery. Even if a pancreatic abnormality is identified before the onset of symptoms, there are no validated biomarkers that distinguish benign pancreatic lesions from pre-cancerous tumors or early-stage pancreatic cancer. Rather, current clinical diagnosis is based on a pathologist's visual inspection of tissue samples. A proven biomarker panel could dramatically improve PDAC screening in at-risk populations.
PDAC diagnosis is further complicated by limitations of imaging and histopathology and, in some cases, the difficulty of distinguishing PDAC from non-malignant pancreatic diseases. Recent advances in endoscopic ultrasound (EUS) have yielded improved sensitivity for PDAC identification. Nevertheless, differentiating between PDAC and benign disease remains difficult and can require multiple biopsies during multiple procedures. Even after two EUS fine needle aspiration (FNA) biopsy procedures, the diagnosis remains unknown for 7% of all patients with a pancreatic abnormality. This results in diagnostic uncertainty and delays in potentially curative treatment. Thus, a key unmet medical need with immediate clinical utility is an effective diagnostic test that accurately differentiates between PDAC and non-malignant pancreatic disorders such as chronic pancreatitis.
The rapid improvement in imaging quality and the number of imaging procedures (26 million annually in the US) has led to a rise in the identification of potential PDAC precursor lesions such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). Although resection of precursor lesions prior to progression to invasive cancer is associated with better survival, accurate differential diagnosis of which lesions will progress to invasive cancer or harbor already malignant cells is necessary as the morbidity and mortality of surgery can be high. Unfortunately, with current diagnostic techniques the malignant potential of precursor lesions is often uncertain. Therefore, there is an unmet need for methods for the accurate determination of the likelihood of precursor legions developing into PDAC.